Is EXOSC3 p.Ser6Phe (c.17C>T) pathogenic?

EXOSC3 p.Ser6Phe (c.17C>T) is classified Uncertain significance in EXOSC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-14). AlphaMissense: likely benign (0.1269); Ultra-rare (popmax 0.0218%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXOSC3 p.Ser6Phe (c.17C>T)?

EXOSC3 p.Ser6Phe (c.17C>T) is associated with Inborn genetic diseases, pontocerebellar hypoplasia type 1B (ClinVar).

How common is EXOSC3 p.Ser6Phe (c.17C>T) in the general population?

EXOSC3 p.Ser6Phe (c.17C>T) is ultra-rare (popmax 0.0218%, amr) (gnomAD).

What do computational predictors say about EXOSC3 p.Ser6Phe (c.17C>T)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

EXOSC3 p.Ser6Phe

c.17C>T · rs749691951 · VCV1418065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP -3.1
Regional constraint	o/e 1.09	unconstrained · MANE · 4,362 bp · p 0.097 · regional, not allelic
Overall
CADD	12.93	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0218% Admixed American · 13/59,700 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00206% 33/1,599,440 alleles · ultra-rare exomes 21/1,447,196 · genomes 12/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0218%	4,592
Remaining individualsnot grpmax-eligible	0.00486%	20,579
European (non-Finnish)	0.00137%	73,196
South Asian	0.0011%	90,694

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EXOSC3
Protein: p.Ser6Phe
Coding: c.17C>T
MANE Select: NM_016042
dbSNP: rs749691951
Type: single nucleotide variant
Location: chr9:37785028 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 8 PDB

Full EXOSC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia type 1B

Similar variants

EXOSC3 p.Ser6Cys Uncertain significance ★★ ⚠ same residue
EXOSC3 p.Arg186Ter Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Asp132Ala Pathogenic ★★ same condition
EXOSC3 p.Gly191Asp Likely pathogenic ★★ same condition
EXOSC3 p.Gly31Ala Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Val80Phe Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/exosc3-p-ser6phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown